BAG-1 is a novel cytoplasmic binding partner of the membrane form of heparin-binding EGF-like growth factor: a unique role for proHB-EGF in cell survival regulation.
Several cell functions related to growth and survival regulation have been attributed specifically to the membrane form of heparin-binding EGF-like growth factor (proHB-EGF), rather than to the diffusible, processed HB-EGF isoform. These findings suggest the existence of a functional binding partner specifically for the membrane form of the growth factor. ... In this study we have identified the prosurvival cochaperone, BAG-1, as a protein that interacts with the cytoplasmic tail domain of proHB-EGF. Interaction between BAG-1 and the 24-amino acid proHB-EGF cytoplasmic tail was initially identified in a yeast two-hybrid screen and was confirmed in mammalian cells. The proHB-EGF tail bound BAG-1 in an hsp70-independent manner and within a 97-amino acid segment that includes the ubiquitin homology domain in BAG-1 but does not include the hsp70 binding site. Effects of BAG-1 and proHB-EGF co-expression were demonstrated in cell adhesion and cell survival assays and in quantitative assays of regulated secretion of soluble HB-EGF. Because the BAG-1 binding site is not present on the mature, diffusible form of the growth factor, these findings suggest a new mechanism by which proHB-EGF, in isolation from the diffusible form, can mediate cell signaling events. In addition, because effects of BAG-1 on regulated secretion of soluble HB-EGF were also identified, this interaction has the potential to alter the signaling capabilities of both the membrane-anchored and the diffusible forms of the growth factor.
Mesh Terms:
Animals, Apoptosis, Binding Sites, CHO Cells, COS Cells, Carrier Proteins, Cell Adhesion, Cell Division, Cell Membrane, Cell Survival, Cricetinae, Cytoplasm, DNA-Binding Proteins, Dose-Response Relationship, Drug, Epidermal Growth Factor, Etoposide, Glutathione Transferase, HSP70 Heat-Shock Proteins, Heparin, Humans, Microscopy, Confocal, Nucleic Acid Synthesis Inhibitors, Protein Binding, Protein Isoforms, Protein Structure, Tertiary, Recombinant Fusion Proteins, Time Factors, Transcription Factors, Transfection, Tumor Cells, Cultured, Two-Hybrid System Techniques, Ubiquitins
Animals, Apoptosis, Binding Sites, CHO Cells, COS Cells, Carrier Proteins, Cell Adhesion, Cell Division, Cell Membrane, Cell Survival, Cricetinae, Cytoplasm, DNA-Binding Proteins, Dose-Response Relationship, Drug, Epidermal Growth Factor, Etoposide, Glutathione Transferase, HSP70 Heat-Shock Proteins, Heparin, Humans, Microscopy, Confocal, Nucleic Acid Synthesis Inhibitors, Protein Binding, Protein Isoforms, Protein Structure, Tertiary, Recombinant Fusion Proteins, Time Factors, Transcription Factors, Transfection, Tumor Cells, Cultured, Two-Hybrid System Techniques, Ubiquitins
J. Biol. Chem.
Date: Aug. 10, 2001
PubMed ID: 11340068
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